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Anti-sclerostin antibodies: Utility in treatment of osteoporosis
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MAT-6160; No. of Pages 6
Maturitas xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Mini Review
Anti-sclerostin antibodies: Utility in treatment of osteoporosis Bart L. Clarke ∗ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN, United States
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Article history: Received 22 April 2014 Accepted 23 April 2014 Available online xxx Keywords: Romosozumab Blosozumab Sclerostin Anti-sclerostin antibody Osteoporosis Treatment
a b s t r a c t Monoclonal antibodies to molecular targets important for bone formation and bone resorption are being investigated for treatment of postmenopausal osteoporosis. Postmenopausal osteoporosis is characterized by increased bone turnover, with bone resorption typically exceeding bone formation. These pathophysiological changes cause decreased bone mineral density and disruption of bone microarchitecture which lead to low-trauma fractures. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes that has been recognized as a new target for therapeutic intervention in patients with osteoporosis. Sclerostin was first recognized when disorders with inactivating mutations of the sclerostin gene SOST were found to be associated with high bone mass. These observations suggested that inhibitors of sclerostin might be used to increase bone mineral density. Romosozumab (AMG 785) is the first humanized anti-sclerostin monoclonal antibody that has been demonstrated to increase bone formation. This investigational monoclonal antibody, and blosozumab, another investigational anti-sclerostin antibody, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies have shown that romosozumab increases bone formation and BMD. Further evaluation of the efficacy and safety of this agent in a large phase III controlled study is awaited. Phase I clinical trial data have recently been published with blosozumab. These novel interventions appear to be promising agents for the treatment of osteoporosis. © 2014 Published by Elsevier Ireland Ltd.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Romosozumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Phase II study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Phase I studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Pre-clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Effect on aged ovariectomized rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Effect on aged male rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Effect on normal female primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Effect on bone quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6. Metaphyseal and fracture healing in rodents and primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.7. Effect on diabetic rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8. Effect on rat model of osteogenesis imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9. Effect on bisphosphonate-pretreated rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blosozumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Postmenopausal osteoporosis is a disorder characterized by high bone turnover, with bone resorption exceeding bone formation, which results in decreased bone mineral density (BMD) and disruption of bone microarchitecture leading to fragility fractures [1,2]. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes that has been recognized as a newly identified target for therapeutic intervention in patients with osteoporosis [3]. Sclerostin was first recognized as a molecular target for treatment of osteoporosis when disorders with inactivating mutations of the sclerostin gene SOST were found to be associated with high bone mass [4,5]. These observations suggested that inhibitors of sclerostin might be used to increase BMD. Romosozumab (AMG 785) is the first humanized anti-sclerostin monoclonal antibody that has been shown to increase bone formation. This investigational monoclonal antibody, and blosozumab, another investigational anti-sclerostin antibody, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies have shown that romosozumab increases bone formation and BMD. Further evaluation of the efficacy and safety of this agent in a large phase III controlled study is awaited. Phase I clinical trial data have recently been published with blosozumab. This mini-review summarizes the published data on the antisclerostin antibodies romosozumab and blosozumab. Most of the studies reviewed focus on romosozumab because this agent is farther along in the development process. These novel interventions appear to be promising agents for the treatment of osteoporosis. 2. Romosozumab 2.1. Phase II study A phase II, multicenter, international, randomized, placebocontrolled, parallel-group, eight-group study evaluated the efficacy and safety of romosozumab over 12 months in 419 postmenopausal women aged 55–85 years who had low BMD [6]. Low BMD was defined as a T-score of −2.0 or less at the lumbar spine, total hip, or femoral neck, and −3.5 or more at each of the three sites. Participants received monthly doses of 70 mg, 140 mg, or 210 mg of subcutaneous romosozumab, or 3-monthly doses of 140 mg or 210 mg of subcutaneous romosozumab, subcutaneous placebo, the open-label active comparator oral alendronate at 70 mg weekly, or subcutaneous teriparatide at 20 g each day. The primary end point was the percentage change from baseline in BMD at the lumbar spine at 12 months. Secondary end points included percentage changes in BMD at other sites and in markers of bone turnover. All dose levels of romosozumab were associated with significant increases in BMD at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo, and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in BMD at the total hip and femoral neck, as well as transient increases in bone formation markers and sustained decreases in a bone-resorption marker. Adverse events were similar among
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treatment groups, except for mild injection-site reactions with romosozumab that generally did not recur. The accompanying commentary to this phase II study by Becker [7] noted that, compared with baseline, BMD was significantly improved for all doses of romosozumab and at all sites except at the distal third of the radius, which remained essentially unchanged. The commentary emphasized that, at the highest monthly dose of romosozumab, increases in BMD at the spine and hip were rapid and robust, surpassing the BMD increase seen with alendronate and teriparatide at 6 months. These increases remained significantly higher than the BMD values with either alendronate or teriparatide by the end of the trial. One of the surprises of the study was that the changes in bone turnover markers were unexpected. Levels of bone-formation markers increased rapidly after the first dose of romosozumab, but then declined, and by month 6, bone-formation markers were nearly back to baseline despite continued treatment. Markers of bone resorption surprisingly declined during the first week and remained suppressed for the duration of the trial. These findings suggested that romosozumab simultaneously transiently stimulated new bone formation and chronically suppressed bone resorption over the 12-month study interval, which is unprecedented among available single-agent therapies for osteoporosis. Combination therapy with teriparatide and potent but intermittently dosed antiresorptive agents such as zoledronic acid [8] or denosumab [9] administered one or two times per year has shown promising similar results. It is not yet clear that the impressive changes in BMD seen with romosozumab will lead to fracture reduction. Safety of longer-term treatment is also not yet known. Significant stimulation of bone formation over more than one year could potentially cause or worsen skeletal complications such as compression neuropathies or spinal stenosis. The optimal duration of treatment is not yet known. The phase III 3-year clinical trial with romosozumab in postmenopausal osteoporotic women (ClinicalTrials.gov #NCT01631214) will hopefully answer these questions. 2.2. Phase I studies Padhi et al. [10] performed a double-blind, placebo-controlled, randomized, ascending multiple-dose study with 32 postmenopausal women and 16 healthy men with low BMD over 12 weeks. Women received six doses of 1 or 2 mg/kg once every 2 weeks, or three doses of 2 or 3 mg/kg once every 4 weeks, or placebo, and men received 1 mg/kg once every 2 weeks, or 3 mg/kg once every 4 weeks, or placebo. Mean serum romosozumab exposure increased approximately proportionately to the dose received. Romosozumab increased the bone formation marker serum type 1 aminoterminal propeptide (PINP) by 66–147%, decreased the bone resorption marker serum C-telopeptide (sCTX) by 15–50%, and increased lumbar spine BMD by 4–7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. Padhi et al. [11] performed the first in-human phase I study with romosozumab (AMG 785) in healthy men and postmenopausal women. In this randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG
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785 or placebo in a 3:1 ratio subcutaneously as 0.1, 0.3, 1, 3, 5, or 10 mg/kg, or intravenously as 1 or 5 mg/kg. Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability and pharmacokinetics, bone turnover markers, and BMD were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis resolved over several weeks. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers serum type 1 aminoterminal propeptide (PINP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in BMD of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, two of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. These findings suggested that single doses of AMG 785 were generally well tolerated. 2.3. Pre-clinical studies 2.3.1. Mechanism of action Although the exact molecular mechanism by which sclerostin exerts its antagonistic effects on Wnt signaling in bone-forming osteoblasts remains unclear, van Dinther et al. [12] showed that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, required the Wnt co-receptors LRP5 and LRP6. Sclerostin was previously shown to not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with [(125)I]sclerostin identified LRP6 as the main specific sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with sclerostin fused to recombinant green fluorescent protein (GFP), this complex was internalized, likely via a clathrin-dependent process, and subsequently degraded in a temperature and proteosome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused sclerostin. Exposure of cells to an anti-sclerostin antibody inhibited the internalization of sclerostinGFP and binding of sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of sclerostin on canonical Wntinduced responses. 2.3.2. Effect on aged ovariectomized rats Li et al. [13] used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 year to allow for significant estrogen deficiencyinduced bone loss, at which point Scl-AbII was administered for 5 weeks. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 year of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. 2.3.3. Effect on aged male rats Li et al. [14] evaluated the effects of sclerostin inhibition by treatment with a sclerostin antibody (Scl-AbII) on bone formation, bone mass, and bone strength in an aged, gonad-intact male rat model. Sixteen-month-old male Sprague-Dawley rats were injected
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subcutaneously with vehicle or Scl-AbII at 5 or 25 mg/kg twice per week for 5 weeks (9–10/group). In vivo dual-energy X-ray absorptiometry (DXA) analysis showed that there was a marked increase in areal BMD of the L1–L5 lumbar vertebrae and long bones (femur and tibia) in both the 5 and 25 mg/kg Scl-AbII-treated groups compared with baseline or vehicle controls at 3 and 5 weeks after treatment. Ex-vivo micro-computed tomographic (CT) analysis demonstrated improved trabecular and cortical architecture at the fifth lumbar vertebral body (L5), femoral diaphysis (FD), and femoral neck (FN) in both Scl-AbII dose groups compared with vehicle controls. The increased cortical and trabecular bone mass was associated with a significantly higher maximal load of L5, FD, and FN in the high-dose group. Bone-formation parameters (i.e., mineralizing surface, mineral apposition rate, and bone-formation rate) at the proximal tibial metaphysis and tibial shaft were markedly greater on trabecular, periosteal, and endocortical surfaces in both Scl-AbII dose groups compared with controls. These results were interpreted as indicating that sclerostin inhibition by treatment with a sclerostin antibody increased bone formation, bone mass, and bone strength in aged male rats. 2.3.4. Effect on normal female primates Ominsky et al. [15] explored the effects of sclerostin inhibition in primates by administering a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content and/or BMD at the femoral neck, radial metaphysis, and tibial metaphysis. These increases, expressed as percent changes from baseline, were 11–29% higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. 2.3.5. Effect on bone quality Scl-Ab treatment is known to dramatically increase bone mass but little is known about the quality of the bone formed during treatment. Ross et al. [16] evaluated global mineralization of bone matrix in rats and nonhuman primates treated with vehicle or Scl-Ab, assayed by backscattered scanning electron microscopy (bSEM) to quantify the BMD distribution (BMDD). Additionally, fluorochrome labeling allowed tissue-age specific measurements to be made in the primate model with Fourier-transform infrared microspectroscopy to determine the kinetics of mineralization, carbonate substitution, crystallinity and collagen cross-linking. Despite up to 54% increases in the bone volume following SclAb treatment, the mean global mineralization of trabecular and cortical bone was unaffected in both animal models investigated. However, there were two subtle changes in the BMDD following Scl-Ab treatment in the primate trabecular bone, including an increase in the number of pixels with a low mineralization value and a decrease in the standard deviation of the distribution. Tissueage specific measurements in the primate model showed that Scl-Ab treatment did not affect the mineral-to-matrix ratio, crystallinity or collagen cross-linking in the endocortical, intracortical, or trabecular compartments. Scl-Ab treatment was associated with a non-significant trend toward accelerated mineralization intracortically, and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment (p < 0.001). These
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findings were interpreted as indicating that Scl-Ab treatment did not negatively impact bone matrix quality. 2.3.6. Metaphyseal and fracture healing in rodents and primates Sclerostin expression is upregulated in unloaded bone and downregulated by loading of bone. Agholme et al. [17] assessed whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model. Ten-week-old male rats (n = 48) were divided into four groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A. Three days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive botulinum toxin A injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma. Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force. These results showed that Scl-Ab increased bone formation and screw fixation to a similar degree in loaded and unloaded bone. In order to further evaluate the potential of anti-sclerostin antibody (Scl-Ab) to improve healing in a bone defect model, Alaee et al. [18] evaluated Scl-Ab in a 3 mm femoral defect in young male outbred rats. Scl-Ab was given either continuously for 6 or 12 weeks after surgery or with 2 weeks of delay for 10 weeks. Bone formation was assessed by radiographs, -CT, and histology. Complete bony union was achieved in only a few defects after 12 weeks of healing (Scl-Ab treated 5/30, vehicle treated 1/15). -CT evaluation demonstrated a significant increase in the BV/TV in the defect in the delayed treatment group (65%, p < 0.05), but a non-significant increase in the continuous group (35%, p = 0.11) compared to control. However, both regimens induced an anabolic response in the bone proximal and distal to the defect and in the un-operated femurs. This study was interpreted as showing that treatment with Scl-Ab can enhance bone repair in a bone defect and in the surrounding host bone, but lacked the osteoinductive activity to heal it, and that this agent seemed to be most effective in bone repair scenarios where there is cortical integrity. Virk et al. [19] evaluated whether systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats. Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The Scl-Ab treatment groups included the continuous Scl-Ab group (21 animals), the early Scl-Ab group (15 animals), and the delayed Scl-Ab group (15 animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0–12; weeks 0–2; and weeks 2–4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at 0, 2, 6, and 12 weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for 12 weeks (15 rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis. In the primary study, four of 15 defects in the continuous (0–12 week) Scl-Ab group, three of 15 defects in the early (0–2 week) Scl-Ab group, and four of 15 defects in the delayed (2–4 week) Scl-Ab group healed at 12 weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for 12 weeks demonstrated a significant increase in new bone formation (p < 0.05) compared
with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls. The study concluded that administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by 12 weeks. Cui et al. [20] investigated the time-dependent changes during Scl-Ab treatment in a mouse osteotomy model. One day after osteotomy, C57BL mice received subcutaneous injection with vehicle or Scl-Ab at 25 mg/kg, twice/week for 2, 4, or 6 weeks. Twenty mice from each group were necropsied at weeks 2, 4, and 6 for micro-CT, histomorphometry, and mechanical testing examinations. The bone mineral apposition rate at fracture callus was significantly higher in the Scl-Ab treated groups at all the time points. Micro-CT analysis showed that the volumetric bone mineral density (vBMD) and bone volume over tissue volume (BV/TV) in the Scl-Ab treated groups at 4 and 6 weeks were significantly greater than that of vehicle control groups. Mechanical testing showed that the maximum load of failure at the fracture callus increased significantly by 68% at 6 weeks in the Scl-Ab treated groups. This study confirmed that mice treated with Scl-Ab increased bone formation from 2 weeks, bone mineral density and bone volume at 4 weeks, followed by significant increase in bone strength at the fracture site at 6 weeks. The results were interpreted as suggesting that sclerostin antibody given at an early stage of fracture healing might promote fracture healing. Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Ominsky et al. [21] investigated the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results were interpreted as supporting the potential for systemic Scl-Ab administration to enhance fracture healing in patients. 2.3.7. Effect on diabetic rats Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. Zucker Diabetic Fatty (ZDF) (fa/fa) rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. Hamann et al. [22] tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits of diabetic ZDF rats. Femoral defects of 3 mm were created in 11-week-old diabetic ZDF fa/fa and nondiabetic ZDF+/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl-AbVI was administered subcutaneously twice weekly for 12 weeks (n = 9–10/group). Bone mass and strength were assessed using pQCT, micro-computed tomography (CT), and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by CT. Diabetic rats displayed lower spinal and femoral bone mass compared to nondiabetic rats, and Scl-AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl-AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load
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at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased by sixfold, consistent with a pronounced anabolic effect. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled only 21% (p < 0.05). Scl-AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). The study concluded that sclerostin antibody treatment reversed the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improved bone defect regeneration in rats. 2.3.8. Effect on rat model of osteogenesis imperfecta Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Sinder et al. [23] evaluated Scl-Ab therapy in mice heterozygous for a typical OI-causing Gly → Cys substitution in col1agen A1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in wild type (WT) mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. This study was interpreted as showing that short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation, and that Scl-Ab may represent a potential new therapy to improve bone mass and reduce fractures in pediatric OI. 2.3.9. Effect on bisphosphonate-pretreated rats Clinical studies previously revealed blunting of the bone anabolic effects of parathyroid hormone treatment in osteoporotic patients in the setting of pre- or cotreatment with the antiresorptive agent alendronate. Li et al. [24] examined the influence of pretreatment or cotreatment with alendronate on the bone anabolic actions of Scl-Ab in ovariectomized rats. Ten-month-old osteopenic ovariectomized rats were treated with alendronate or vehicle for 6 week, before the start of Scl-Ab treatment. Alendronate-pretreated ovariectomized rats were switched to SclAb alone or to a combination of alendronate and Scl-Ab for another 6 week. Vehicle-pretreated ovariectomized rats were switched to Scl-Ab or continued on vehicle to serve as controls. Scl-Ab treatment increased areal BMD, volumetric BMD, trabecular and cortical bone mass, and bone strength similarly in ovariectomized rats pretreated with alendronate or vehicle. Serum osteocalcin and bone formation rate on trabecular, endocortical, and periosteal surfaces responded similarly to Scl-Ab in alendronate or vehicle-pretreated ovariectomized rats. Furthermore, co-treatment with alendronate did not have significant effects on the increased bone formation, bone mass, and bone strength induced by Scl-Ab in the ovariectomized rats that were pretreated with alendronate. These results were interpreted as indicating that the increases in bone formation, bone mass, and bone strength with Scl-Ab treatment were not affected by pre- or co-treatment with alendronate in ovariectomized rats with established osteopenia.
5
weeks, multiple subcutaneous doses of up to 270 mg every 2 weeks for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study and 12 to placebo, and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, serum type 1 aminoterminal propeptide (PINP), bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and BMD after single and up to 5 administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior bisphosphonate use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. The findings suggested that blosozumab was well tolerated and exhibited anabolic effects on bone. 4. Conclusion The studies presented in this mini-review suggest that antisclerostin antibodies show great promise as agents to treat postmenopausal and other forms of osteoporosis, and possibly to shorten fracture healing time, improve callus strength, and prevent orthopedic hardware loosening. Romosozumab is fairly far along in clinical development, whereas blosozumab has one report of two phase I studies published to date. A phase III study with romosozumab is nearing completion, with results expected within the next several years. Further clinical studies are underway to demonstrate the efficacy and safety of these monoclonal antibodies in postmenopausal osteoporosis, and for possible application to other clinical settings. Contributors The author has solely contributed to the design, writing, and editing of this mini-review, submitted at the invitation of the Editor-in-Chief, Dr. Margaret Rees. Competing interests The author has no competing interests to declare. Funding No funding was received to support the writing of this manuscript. Provenance and peer review Commissioned and externally peer reviewed.
3. Blosozumab McColm et al. [25] performed two phase 1 clinical studies to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple intravenous and subcutaneous doses of blosozumab in postmenopausal women, including prior or current bisphosphonate users. In these randomized, subject- and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single intravenous doses of up to 750 mg, single subcutaneous doses of 150 mg, multiple intravenous doses of up to 750 mg every 2 weeks for 8
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[6] McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370: 412–20. [7] Becker CB. Sclerostin inhibition for osteoporosis – a new approach. N Engl J Med 2014;370:476–7. [8] Cosman F, Eriksen EF, Recknor C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res 2011;26:503–11. [9] Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382:50–6. [10] Padhi D, Allison M, Kivitz AJ, et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol 2013 [Epub ahead of print, November 23]. [11] Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 2011;26:19–26. [12] van Dinther M, Zhang J, Weidauer SE, et al. Anti-sclerostin antibody inhibits internalization of sclerostin and sclerostin-mediated antagonism of Wnt/LRP6 signaling. PLoS ONE 2013;8:e62295. [13] Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2009;24:578–88. [14] Li X, Warmington KS, Niu QT, et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J Bone Miner Res 2010;25:2647–56. [15] Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 2010;25:948–59.
[16] Ross RD, Edwards LH, Acerbo AS, et al. Bone matrix quality following sclerostin antibody treatment. J Bone Miner Res 2014 [Epub ahead of print, January 28]. [17] Agholme F, Isaksson H, Li X, Ke HZ, Aspenberg P. Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats. Acta Orthop 2011;82:628–32. [18] Alaee F, Virk MS, Tang H, et al. Evaluation of the effects of systemic treatment with a sclerostin neutralizing antibody on bone repair in a rat femoral defect model. J Orthop Res 2014;32:197–203. [19] Virk MS, Alaee F, Tang H, Ominsky MS, Ke HZ, Lieberman JR. Systemic administration of sclerostin antibody enhances bone repair in a critical-sized femoral defect in a rat model. J Bone Joint Surg Am 2013;95:694–701. [20] Cui L, Cheng H, Song C, et al. Time-dependent effects of sclerostin antibody on a mouse fracture healing model. J Musculoskelet Neuronal Interact 2013;13:178–84. [21] Ominsky MS, Li C, Li X, et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J Bone Miner Res 2011;26:1012–21. [22] Hamann C, Rauner M, Höhna Y, et al. Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res 2013;28:627–38. [23] Sinder BP, Eddy MM, Ominsky MS, Caird MS, Marini JC, Kozloff KM. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J Bone Miner Res 2013;28:73–80. [24] Li X, Ominsky MS, Warmington KS, et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats. Endocrinology 2011;152:3312–22. [25] McColm J, Hu L, Womack T, Tang CC, Chiang AY. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res 2014;29:935–43.
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Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Mini Review
Anti-sclerostin antibodies: Utility in treatment of osteoporosis Bart L. Clarke ∗ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN, United States
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Article history: Received 22 April 2014 Accepted 23 April 2014 Available online xxx Keywords: Romosozumab Blosozumab Sclerostin Anti-sclerostin antibody Osteoporosis Treatment
a b s t r a c t Monoclonal antibodies to molecular targets important for bone formation and bone resorption are being investigated for treatment of postmenopausal osteoporosis. Postmenopausal osteoporosis is characterized by increased bone turnover, with bone resorption typically exceeding bone formation. These pathophysiological changes cause decreased bone mineral density and disruption of bone microarchitecture which lead to low-trauma fractures. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes that has been recognized as a new target for therapeutic intervention in patients with osteoporosis. Sclerostin was first recognized when disorders with inactivating mutations of the sclerostin gene SOST were found to be associated with high bone mass. These observations suggested that inhibitors of sclerostin might be used to increase bone mineral density. Romosozumab (AMG 785) is the first humanized anti-sclerostin monoclonal antibody that has been demonstrated to increase bone formation. This investigational monoclonal antibody, and blosozumab, another investigational anti-sclerostin antibody, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies have shown that romosozumab increases bone formation and BMD. Further evaluation of the efficacy and safety of this agent in a large phase III controlled study is awaited. Phase I clinical trial data have recently been published with blosozumab. These novel interventions appear to be promising agents for the treatment of osteoporosis. © 2014 Published by Elsevier Ireland Ltd.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Romosozumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Phase II study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Phase I studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Pre-clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Effect on aged ovariectomized rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Effect on aged male rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Effect on normal female primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Effect on bone quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6. Metaphyseal and fracture healing in rodents and primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.7. Effect on diabetic rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8. Effect on rat model of osteogenesis imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9. Effect on bisphosphonate-pretreated rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blosozumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Tel.: +1 507 266 4322; fax: +1 507 284 5745. E-mail address: [email protected] http://dx.doi.org/10.1016/j.maturitas.2014.04.016 0378-5122/© 2014 Published by Elsevier Ireland Ltd.
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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Postmenopausal osteoporosis is a disorder characterized by high bone turnover, with bone resorption exceeding bone formation, which results in decreased bone mineral density (BMD) and disruption of bone microarchitecture leading to fragility fractures [1,2]. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes that has been recognized as a newly identified target for therapeutic intervention in patients with osteoporosis [3]. Sclerostin was first recognized as a molecular target for treatment of osteoporosis when disorders with inactivating mutations of the sclerostin gene SOST were found to be associated with high bone mass [4,5]. These observations suggested that inhibitors of sclerostin might be used to increase BMD. Romosozumab (AMG 785) is the first humanized anti-sclerostin monoclonal antibody that has been shown to increase bone formation. This investigational monoclonal antibody, and blosozumab, another investigational anti-sclerostin antibody, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies have shown that romosozumab increases bone formation and BMD. Further evaluation of the efficacy and safety of this agent in a large phase III controlled study is awaited. Phase I clinical trial data have recently been published with blosozumab. This mini-review summarizes the published data on the antisclerostin antibodies romosozumab and blosozumab. Most of the studies reviewed focus on romosozumab because this agent is farther along in the development process. These novel interventions appear to be promising agents for the treatment of osteoporosis. 2. Romosozumab 2.1. Phase II study A phase II, multicenter, international, randomized, placebocontrolled, parallel-group, eight-group study evaluated the efficacy and safety of romosozumab over 12 months in 419 postmenopausal women aged 55–85 years who had low BMD [6]. Low BMD was defined as a T-score of −2.0 or less at the lumbar spine, total hip, or femoral neck, and −3.5 or more at each of the three sites. Participants received monthly doses of 70 mg, 140 mg, or 210 mg of subcutaneous romosozumab, or 3-monthly doses of 140 mg or 210 mg of subcutaneous romosozumab, subcutaneous placebo, the open-label active comparator oral alendronate at 70 mg weekly, or subcutaneous teriparatide at 20 g each day. The primary end point was the percentage change from baseline in BMD at the lumbar spine at 12 months. Secondary end points included percentage changes in BMD at other sites and in markers of bone turnover. All dose levels of romosozumab were associated with significant increases in BMD at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo, and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in BMD at the total hip and femoral neck, as well as transient increases in bone formation markers and sustained decreases in a bone-resorption marker. Adverse events were similar among
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treatment groups, except for mild injection-site reactions with romosozumab that generally did not recur. The accompanying commentary to this phase II study by Becker [7] noted that, compared with baseline, BMD was significantly improved for all doses of romosozumab and at all sites except at the distal third of the radius, which remained essentially unchanged. The commentary emphasized that, at the highest monthly dose of romosozumab, increases in BMD at the spine and hip were rapid and robust, surpassing the BMD increase seen with alendronate and teriparatide at 6 months. These increases remained significantly higher than the BMD values with either alendronate or teriparatide by the end of the trial. One of the surprises of the study was that the changes in bone turnover markers were unexpected. Levels of bone-formation markers increased rapidly after the first dose of romosozumab, but then declined, and by month 6, bone-formation markers were nearly back to baseline despite continued treatment. Markers of bone resorption surprisingly declined during the first week and remained suppressed for the duration of the trial. These findings suggested that romosozumab simultaneously transiently stimulated new bone formation and chronically suppressed bone resorption over the 12-month study interval, which is unprecedented among available single-agent therapies for osteoporosis. Combination therapy with teriparatide and potent but intermittently dosed antiresorptive agents such as zoledronic acid [8] or denosumab [9] administered one or two times per year has shown promising similar results. It is not yet clear that the impressive changes in BMD seen with romosozumab will lead to fracture reduction. Safety of longer-term treatment is also not yet known. Significant stimulation of bone formation over more than one year could potentially cause or worsen skeletal complications such as compression neuropathies or spinal stenosis. The optimal duration of treatment is not yet known. The phase III 3-year clinical trial with romosozumab in postmenopausal osteoporotic women (ClinicalTrials.gov #NCT01631214) will hopefully answer these questions. 2.2. Phase I studies Padhi et al. [10] performed a double-blind, placebo-controlled, randomized, ascending multiple-dose study with 32 postmenopausal women and 16 healthy men with low BMD over 12 weeks. Women received six doses of 1 or 2 mg/kg once every 2 weeks, or three doses of 2 or 3 mg/kg once every 4 weeks, or placebo, and men received 1 mg/kg once every 2 weeks, or 3 mg/kg once every 4 weeks, or placebo. Mean serum romosozumab exposure increased approximately proportionately to the dose received. Romosozumab increased the bone formation marker serum type 1 aminoterminal propeptide (PINP) by 66–147%, decreased the bone resorption marker serum C-telopeptide (sCTX) by 15–50%, and increased lumbar spine BMD by 4–7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. Padhi et al. [11] performed the first in-human phase I study with romosozumab (AMG 785) in healthy men and postmenopausal women. In this randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG
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785 or placebo in a 3:1 ratio subcutaneously as 0.1, 0.3, 1, 3, 5, or 10 mg/kg, or intravenously as 1 or 5 mg/kg. Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability and pharmacokinetics, bone turnover markers, and BMD were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis resolved over several weeks. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers serum type 1 aminoterminal propeptide (PINP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in BMD of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, two of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. These findings suggested that single doses of AMG 785 were generally well tolerated. 2.3. Pre-clinical studies 2.3.1. Mechanism of action Although the exact molecular mechanism by which sclerostin exerts its antagonistic effects on Wnt signaling in bone-forming osteoblasts remains unclear, van Dinther et al. [12] showed that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, required the Wnt co-receptors LRP5 and LRP6. Sclerostin was previously shown to not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with [(125)I]sclerostin identified LRP6 as the main specific sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with sclerostin fused to recombinant green fluorescent protein (GFP), this complex was internalized, likely via a clathrin-dependent process, and subsequently degraded in a temperature and proteosome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused sclerostin. Exposure of cells to an anti-sclerostin antibody inhibited the internalization of sclerostinGFP and binding of sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of sclerostin on canonical Wntinduced responses. 2.3.2. Effect on aged ovariectomized rats Li et al. [13] used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 year to allow for significant estrogen deficiencyinduced bone loss, at which point Scl-AbII was administered for 5 weeks. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 year of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. 2.3.3. Effect on aged male rats Li et al. [14] evaluated the effects of sclerostin inhibition by treatment with a sclerostin antibody (Scl-AbII) on bone formation, bone mass, and bone strength in an aged, gonad-intact male rat model. Sixteen-month-old male Sprague-Dawley rats were injected
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subcutaneously with vehicle or Scl-AbII at 5 or 25 mg/kg twice per week for 5 weeks (9–10/group). In vivo dual-energy X-ray absorptiometry (DXA) analysis showed that there was a marked increase in areal BMD of the L1–L5 lumbar vertebrae and long bones (femur and tibia) in both the 5 and 25 mg/kg Scl-AbII-treated groups compared with baseline or vehicle controls at 3 and 5 weeks after treatment. Ex-vivo micro-computed tomographic (CT) analysis demonstrated improved trabecular and cortical architecture at the fifth lumbar vertebral body (L5), femoral diaphysis (FD), and femoral neck (FN) in both Scl-AbII dose groups compared with vehicle controls. The increased cortical and trabecular bone mass was associated with a significantly higher maximal load of L5, FD, and FN in the high-dose group. Bone-formation parameters (i.e., mineralizing surface, mineral apposition rate, and bone-formation rate) at the proximal tibial metaphysis and tibial shaft were markedly greater on trabecular, periosteal, and endocortical surfaces in both Scl-AbII dose groups compared with controls. These results were interpreted as indicating that sclerostin inhibition by treatment with a sclerostin antibody increased bone formation, bone mass, and bone strength in aged male rats. 2.3.4. Effect on normal female primates Ominsky et al. [15] explored the effects of sclerostin inhibition in primates by administering a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content and/or BMD at the femoral neck, radial metaphysis, and tibial metaphysis. These increases, expressed as percent changes from baseline, were 11–29% higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. 2.3.5. Effect on bone quality Scl-Ab treatment is known to dramatically increase bone mass but little is known about the quality of the bone formed during treatment. Ross et al. [16] evaluated global mineralization of bone matrix in rats and nonhuman primates treated with vehicle or Scl-Ab, assayed by backscattered scanning electron microscopy (bSEM) to quantify the BMD distribution (BMDD). Additionally, fluorochrome labeling allowed tissue-age specific measurements to be made in the primate model with Fourier-transform infrared microspectroscopy to determine the kinetics of mineralization, carbonate substitution, crystallinity and collagen cross-linking. Despite up to 54% increases in the bone volume following SclAb treatment, the mean global mineralization of trabecular and cortical bone was unaffected in both animal models investigated. However, there were two subtle changes in the BMDD following Scl-Ab treatment in the primate trabecular bone, including an increase in the number of pixels with a low mineralization value and a decrease in the standard deviation of the distribution. Tissueage specific measurements in the primate model showed that Scl-Ab treatment did not affect the mineral-to-matrix ratio, crystallinity or collagen cross-linking in the endocortical, intracortical, or trabecular compartments. Scl-Ab treatment was associated with a non-significant trend toward accelerated mineralization intracortically, and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment (p < 0.001). These
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findings were interpreted as indicating that Scl-Ab treatment did not negatively impact bone matrix quality. 2.3.6. Metaphyseal and fracture healing in rodents and primates Sclerostin expression is upregulated in unloaded bone and downregulated by loading of bone. Agholme et al. [17] assessed whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model. Ten-week-old male rats (n = 48) were divided into four groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A. Three days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive botulinum toxin A injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma. Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force. These results showed that Scl-Ab increased bone formation and screw fixation to a similar degree in loaded and unloaded bone. In order to further evaluate the potential of anti-sclerostin antibody (Scl-Ab) to improve healing in a bone defect model, Alaee et al. [18] evaluated Scl-Ab in a 3 mm femoral defect in young male outbred rats. Scl-Ab was given either continuously for 6 or 12 weeks after surgery or with 2 weeks of delay for 10 weeks. Bone formation was assessed by radiographs, -CT, and histology. Complete bony union was achieved in only a few defects after 12 weeks of healing (Scl-Ab treated 5/30, vehicle treated 1/15). -CT evaluation demonstrated a significant increase in the BV/TV in the defect in the delayed treatment group (65%, p < 0.05), but a non-significant increase in the continuous group (35%, p = 0.11) compared to control. However, both regimens induced an anabolic response in the bone proximal and distal to the defect and in the un-operated femurs. This study was interpreted as showing that treatment with Scl-Ab can enhance bone repair in a bone defect and in the surrounding host bone, but lacked the osteoinductive activity to heal it, and that this agent seemed to be most effective in bone repair scenarios where there is cortical integrity. Virk et al. [19] evaluated whether systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats. Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The Scl-Ab treatment groups included the continuous Scl-Ab group (21 animals), the early Scl-Ab group (15 animals), and the delayed Scl-Ab group (15 animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0–12; weeks 0–2; and weeks 2–4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at 0, 2, 6, and 12 weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for 12 weeks (15 rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis. In the primary study, four of 15 defects in the continuous (0–12 week) Scl-Ab group, three of 15 defects in the early (0–2 week) Scl-Ab group, and four of 15 defects in the delayed (2–4 week) Scl-Ab group healed at 12 weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for 12 weeks demonstrated a significant increase in new bone formation (p < 0.05) compared
with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls. The study concluded that administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by 12 weeks. Cui et al. [20] investigated the time-dependent changes during Scl-Ab treatment in a mouse osteotomy model. One day after osteotomy, C57BL mice received subcutaneous injection with vehicle or Scl-Ab at 25 mg/kg, twice/week for 2, 4, or 6 weeks. Twenty mice from each group were necropsied at weeks 2, 4, and 6 for micro-CT, histomorphometry, and mechanical testing examinations. The bone mineral apposition rate at fracture callus was significantly higher in the Scl-Ab treated groups at all the time points. Micro-CT analysis showed that the volumetric bone mineral density (vBMD) and bone volume over tissue volume (BV/TV) in the Scl-Ab treated groups at 4 and 6 weeks were significantly greater than that of vehicle control groups. Mechanical testing showed that the maximum load of failure at the fracture callus increased significantly by 68% at 6 weeks in the Scl-Ab treated groups. This study confirmed that mice treated with Scl-Ab increased bone formation from 2 weeks, bone mineral density and bone volume at 4 weeks, followed by significant increase in bone strength at the fracture site at 6 weeks. The results were interpreted as suggesting that sclerostin antibody given at an early stage of fracture healing might promote fracture healing. Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Ominsky et al. [21] investigated the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results were interpreted as supporting the potential for systemic Scl-Ab administration to enhance fracture healing in patients. 2.3.7. Effect on diabetic rats Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. Zucker Diabetic Fatty (ZDF) (fa/fa) rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. Hamann et al. [22] tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits of diabetic ZDF rats. Femoral defects of 3 mm were created in 11-week-old diabetic ZDF fa/fa and nondiabetic ZDF+/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl-AbVI was administered subcutaneously twice weekly for 12 weeks (n = 9–10/group). Bone mass and strength were assessed using pQCT, micro-computed tomography (CT), and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by CT. Diabetic rats displayed lower spinal and femoral bone mass compared to nondiabetic rats, and Scl-AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl-AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load
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at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased by sixfold, consistent with a pronounced anabolic effect. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled only 21% (p < 0.05). Scl-AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). The study concluded that sclerostin antibody treatment reversed the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improved bone defect regeneration in rats. 2.3.8. Effect on rat model of osteogenesis imperfecta Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Sinder et al. [23] evaluated Scl-Ab therapy in mice heterozygous for a typical OI-causing Gly → Cys substitution in col1agen A1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in wild type (WT) mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. This study was interpreted as showing that short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation, and that Scl-Ab may represent a potential new therapy to improve bone mass and reduce fractures in pediatric OI. 2.3.9. Effect on bisphosphonate-pretreated rats Clinical studies previously revealed blunting of the bone anabolic effects of parathyroid hormone treatment in osteoporotic patients in the setting of pre- or cotreatment with the antiresorptive agent alendronate. Li et al. [24] examined the influence of pretreatment or cotreatment with alendronate on the bone anabolic actions of Scl-Ab in ovariectomized rats. Ten-month-old osteopenic ovariectomized rats were treated with alendronate or vehicle for 6 week, before the start of Scl-Ab treatment. Alendronate-pretreated ovariectomized rats were switched to SclAb alone or to a combination of alendronate and Scl-Ab for another 6 week. Vehicle-pretreated ovariectomized rats were switched to Scl-Ab or continued on vehicle to serve as controls. Scl-Ab treatment increased areal BMD, volumetric BMD, trabecular and cortical bone mass, and bone strength similarly in ovariectomized rats pretreated with alendronate or vehicle. Serum osteocalcin and bone formation rate on trabecular, endocortical, and periosteal surfaces responded similarly to Scl-Ab in alendronate or vehicle-pretreated ovariectomized rats. Furthermore, co-treatment with alendronate did not have significant effects on the increased bone formation, bone mass, and bone strength induced by Scl-Ab in the ovariectomized rats that were pretreated with alendronate. These results were interpreted as indicating that the increases in bone formation, bone mass, and bone strength with Scl-Ab treatment were not affected by pre- or co-treatment with alendronate in ovariectomized rats with established osteopenia.
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weeks, multiple subcutaneous doses of up to 270 mg every 2 weeks for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study and 12 to placebo, and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, serum type 1 aminoterminal propeptide (PINP), bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and BMD after single and up to 5 administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior bisphosphonate use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. The findings suggested that blosozumab was well tolerated and exhibited anabolic effects on bone. 4. Conclusion The studies presented in this mini-review suggest that antisclerostin antibodies show great promise as agents to treat postmenopausal and other forms of osteoporosis, and possibly to shorten fracture healing time, improve callus strength, and prevent orthopedic hardware loosening. Romosozumab is fairly far along in clinical development, whereas blosozumab has one report of two phase I studies published to date. A phase III study with romosozumab is nearing completion, with results expected within the next several years. Further clinical studies are underway to demonstrate the efficacy and safety of these monoclonal antibodies in postmenopausal osteoporosis, and for possible application to other clinical settings. Contributors The author has solely contributed to the design, writing, and editing of this mini-review, submitted at the invitation of the Editor-in-Chief, Dr. Margaret Rees. Competing interests The author has no competing interests to declare. Funding No funding was received to support the writing of this manuscript. Provenance and peer review Commissioned and externally peer reviewed.
3. Blosozumab McColm et al. [25] performed two phase 1 clinical studies to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple intravenous and subcutaneous doses of blosozumab in postmenopausal women, including prior or current bisphosphonate users. In these randomized, subject- and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single intravenous doses of up to 750 mg, single subcutaneous doses of 150 mg, multiple intravenous doses of up to 750 mg every 2 weeks for 8
References [1] Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377(9773):1276–87. [2] Canalis E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 2013;9:575–83. [3] Lewiecki EM. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol 2011;7:631–8. [4] Costa AG, Bilezikian JP, Lewiecki EM. Update on romosozumab: a humanized monoclonal antibody to sclerostin. Expert Opin Biol Ther 2014;14:697–707. [5] Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 2012;33:747–83.
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Please cite this article in press as: Clarke BL. Anti-sclerostin antibodies: Utility in treatment of osteoporosis. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.016